Hypertension and Diabetic Kidney Disease Progression Hypertension and Diabetic Kidney Disease Progression

Hypertension and Diabetic Kidney Disease Progression George L. Bakris, MD Professor and Vice-Chairman Dept. of Preventive Medicine Director, Hypertension/Clinical Research Center Rush University Medical Center Chicago, IL 60612 ©2006. American College of Physicians. All Rights Reserved.

Disclosure of Relationships with Commercial Companies:

George L. Bakris, MD, FACP

Research Grants/Contracts: NIH (NIDDK/NHLBI), AstraZeneca, Abbott, Alteon, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Novartis, Lilly, Sankyo

Consultantship: Astra-Zeneca, AusAm, Abbott, Alteon, Biovail, Boehringer-Ingelheim, BMS/Sanofi, GlaxoSmithKline, Merck, Novartis, Lilly

Speakers Bureau: Boehringer-Ingelheim, BMS/Sanofi, GlaxoSmithKline, Merck, Novartis, Lilly

Increasing Prevalence of Diagnosed Diabetes in US Adults Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/diabetes/statistics/prev/state/fig61994and2002.htm. Accessed August 30, 2004. 1994 2002 <4% 4–4.9% 5–5.9%  6% ©2006. American College of Physicians. All Rights Reserved.

Increasing Prevalence of Obesity* Among US Adults Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm. Accessed August 30, 2004. *BMI ≥ 30 kg/m 2 . 10%–14% 15%–19% 20%–24% ≥ 25% 2002 ©2006. American College of Physicians. All Rights Reserved. 1994

Diabetes: The Most Common Cause of ESRD Primary Diagnosis for Patients Who Start Dialysis Glomerulonephritis 13% Other 10% United States Renal Data System. Annual data report. 2000. No. of patients Projection 95% CI 1984 1988 1992 1996 2000 2004 2008 0 100 200 300 400 500 600 700 r 2 =99.8% 243,524 281,355 520,240 No. of dialysis patients (thousands) ©2006. American College of Physicians. All Rights Reserved. Diabetes 50.1% Hypertension 27%

Level of Kidney Function Is an Independent Risk Factor For CV Risk N=15,350 Mean follow-up=6.2 years Age -45-64 Stage of Kidney Disease N Stage 2 (GFR-60-89) 7,665 Stage 3 &4 (GFR-15-59) 444 1.0 1.25 1.75 1.5 2.0 1.38 1.16 Manjunath G et.al JACC 2003;41:47-55 0.75 ©2006. American College of Physicians. All Rights Reserved.

CKD Hospitalization Rates for Cardiovascular Disease

CHF admission rates are 5 times higher in patients with a diagnosis of CKD vs non-CKD

Ischemic heart disease admissions at 2-2.5 times higher in the CKD population

Cardiac arrhythmia admission rates are twice as common in CKD populations

CVD Risk Factors

Hypertension*

Cigarette smoking

Obesity* (BMI > 30 kg/m 2 )

Physical inactivity

Dyslipidemia*

Diabetes mellitus*

Microalbuminuria

Estimated GFR <60 ml/min

Age (older than 55 for men, 65 for women)

Family history of premature CVD

(men under age 55 or women under age 65)

Microalbuminuria Albuminuria (Proteinuria) mg/day  CV Risk and Vascular Dysfunction  CV Risk and Presence of Renal Dysfunction and Vascular Dysfunction Normal ©2006. American College of Physicians. All Rights Reserved.

Proteinuria Predicts Stroke and CHD Events in Type 2 Diabetes P <0.001 40 30 20 10 0 Stroke CHD Events 80 60 40 20 0 0.5 0.6 0.7 0.8 0.9 1 Survival Curves For CV Mortality Overall: P <0.001 C B A Incidence (%) Months Miettinen H et al. Stroke . 1996;27:2033-2039. B: U-Prot 150–300 mg/L A: U-Prot <150 mg/L C: U-Prot >300 mg/L 0 U-Prot = Urinary protein concentration. 100 ©2006. American College of Physicians. All Rights Reserved.

Berton G et.al. Diabetologia, Aug. 2004 Kaplan-Meier curves of 3-year all-cause mortality in the AMI patients stratified by DM status and ACR > 30 µ g/mg or <30 µ g/mg on the 3rd day after admission ©2006. American College of Physicians. All Rights Reserved.

Use of MAU, CRP, and BNP as Predictors of Mortality and CV Events Mortality Hazard Ratio ( 95% CI ) for Values Above 80 th Percentile NT-proBNP CRP MAU First Major CV Event NT-proBNP CRP MAU P=.007 P=014 P=.008 P=.003 P=.96 P=<.001 Adjusted for age, sex, smoking, DM, HTN, Afib, LVEF<50%, LVH, total cholesterol, serum creatinine. Mortality analysis based on 91 deaths, and CV event data based on 63 events due to missing covariates. The 80 th percentile corresponds to values more than 5.85 pg/mL for NT-proBNP, 5.76 mg/L for CRP, and 18.4 mg/g for MAU. Kistorp K, et al. JAMA . 2005;293:1609-1616. ©2006. American College of Physicians. All Rights Reserved. 0 0.5 1 1.5 2 3 4 5

Predictive value of antiproteinuric effect on renal protection 0 -5 5 10 15 -100 -50 0 50 100 Rate of decline in GFR (ml/min/ year) r = 0.47 p < 0.011 delta Proteinuria (% change from pretreatment ) Apperloo AJ et al; Kidney Int 1994; 45:S174-8. Rossing P et al. Diabetologia. 1994;37:511-516. 15 10 5 0 -5 -100 -50 0 50 100 r=0.73 p<.001. Diabetes Non-Diabetes ©2006. American College of Physicians. All Rights Reserved.

Clinical Trials and Renal Outcomes Based on Proteinuria Reduction

Increased Time to Dialysis

(30-35% proteinuria reduction)

Captopril Trial - N Engl J Med, 1993

AASK Trial- JAMA, 2001

RENAAL - N Engl J Med, 2001

IDNT - N Engl J Med, 2001

COOPERATE -Lancet, 2003

No Change in Time to Dialysis

(NO proteinuria reduction)

DHPCCB arm- IDNT

DHPCCB arm- AASK

Hart P & Bakris GL Managing Hypertension in the Diabetic Patient. IN: Egan BM, Basile JN, and Lackland DT (eds.) Hot Topics in Hypertension Hanley and Belfus, Philadelphia, 2004, pp.249-252. ©2006. American College of Physicians. All Rights Reserved.

IDNT Proportion of Patients with the Primary Composite Endpoint* Proportion with primary endpoint 0 6 12 18 24 30 36 42 48 54 579 555 528 496 400 304 216 146 65 565 542 508 474 385 287 187 128 46 568 551 512 471 401 280 190 122 53 Irbesartan (n) Amlodipine (n) Placebo (n) Months of Follow-up *Composite of a doubling of serum creatinine, end stage renal disease, or death P=0.02 for irbesartan compared to placebo Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860. ©2001 Massachusetts Medical Society. All rights reserved. ©2006. American College of Physicians. All Rights Reserved.

Relationship Between Rate of Decline in Renal Function and Change in Proteinuria in IDNT Lewis EJ et al. N Engl J Med . 2001;345:851-860. Amlodipine  Irbesartan Placebo Creatinine clearance (mL/min/1.73 m 2 ) Proteinuria (g/d) ©2006. American College of Physicians. All Rights Reserved. -8 -7 -6 -5 -4 -3 -2 -1 0

RENAAL; Baseline Proteinuria as a Determinant for Cardiac Events in Type 2 diabetes CV Endpoint Heart Failure 0 2 4 6 Hazard ratio 5.25 Albuminuria (g/g) 0 2 4 6 <.5 2.0 2.95 4.4  5.25 Albuminuria (g/g) <.5 2.0 2.95 4.4  Hazard ratio De Zeeuw et al; Circulation 2004 (adjusted for all conventional risk factors) ©2006. American College of Physicians. All Rights Reserved.

RENAAL; Baseline Proteinuria as a Determinant for RENAL Events in Type 2 Diabetes De Zeeuw et al; Kidney Int 2004 Primary composite Endpoint 0 10 15 5 Hazard ratio <.5 2.0 2.95 4.4  5.25        Baseline Albuminuria (g/g) Baseline Albuminuria (g/g) 0 <.5 2.0 2.95 4.4 5.25 ESRD  Hazard ratio (adjusted for all conventional risk factors) ©2006. American College of Physicians. All Rights Reserved. 10 20 30

De Zeeuw D, et al. Kidney Int . 2004; 65:2309.

RENAAL: Renal End Points By 6-Month Changes in Albuminuria 60 50 40 30 20 10 0 % with ERSD 0 12 24 36 48 Month 60 50 40 30 20 10 0 % with renal end point 0 12 24 36 48 Month <0%  0<30%  30% <0%  0<30%  30% Δ Alb:  0<30 vs. <0% Δ Alb:  30 vs. <0% Δ Alb:  30 vs.  0<30% 0.88 0.60 0.68 0.1570 <.0001 0.0003 HR P values Unadjusted Renal End Point 0.76 0.46 0.61 0.0028 <.0001 <.0001 HR P values Adjusted Δ Alb:  0<30 vs. <0% Δ Alb:  30 vs. <0% Δ Alb:  30 vs.  0<30% 0.82 0.51 0.62 0.1242 <.0001 0.0019 HR P values Unadjusted Renal End Point 0.62 0.37 0.60 0.0003 <.0001 <.0010 HR P values Adjusted ©2006. American College of Physicians. All Rights Reserved.

De Zeeuw D, et al. Circulation . 2004;110:921.

RENAAL: Cardiovascular End Points by 6-Month Changes in Albuminuria 40 % with CV endpoints 30 20 10 0 0 12 24 36 48 Month CV Endpoint 40 % with CV endpoints 30 20 10 0 0 12 24 36 48 Month Heart Failure <0% >30% <0% >30% ©2006. American College of Physicians. All Rights Reserved.

Most Common Cause of Failing to Reduce Proteinuria with ACE Inhibitor or ARB

High SALT intake

(>5 grams/day)

What is the Goal BP and Initial Therapy in Kidney Disease or Diabetes to Reduce CV Risk?

Group Goal BP (mmHg) Initial Therapy

Am. Diabetes Assoc (2006) <130/80 ACE Inhibitor or ARB*

KDOQI (NKF) (2004) <130/80 ACE Inhibitor or ARB*

JNC 7 (2003) <130/80 ACE Inhibitor or ARB*

Canadian HTN Soc. (2002) <130/80 ACE Inhibitor or ARB

Am. Diabetes Assoc (2002) <130/80 ACE Inhibitor or ARB

Natl. Kidney Fdn.-CKD(2002) <130/80 ACE Inhibitor or ARB*

Natl. Kidney Fdn. (2000) <130/80 ACE Inhibitor*

British HTN Soc. (1999) <140/80 ACE Inhibitor

WHO/ISH (1999) <130/85 ACE Inhibitor

JNC VI (1997) <130/85 ACE Inhibitor

DETAIL, a prospective, multicenter, non-inferiority trial randomized 250 patients with type 2 diabetes, hypertension (BP <180/95 mm Hg), and evidence of early nephropathy (GFR >70 mL/min/1.73 m2) to either telmisartan or enalapril. Followed for 5 years

Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2 Diabetes and Nephropathy Barnett AH et.al N Engl J Med 2004;351:1952-1961. ©2006. American College of Physicians. All Rights Reserved.

Angiotensin-Receptor Blockade versus Converting–Enzyme Inhibition in Type 2 Diabetes and Nephropathy-RESULTS Barnett AH et.al N Engl J Med 2004;351:1952-1961. Baseline GFR 91 ml/min ©2006. American College of Physicians. All Rights Reserved.

-9.4 -1.3 -4 -7 -10 -8 -6 -4 -2 0 mL/min/yr. mm Hg Initial GFR Rate of Decline [<4 Months] 130 140 150 Systolic Pressure Trial End Bakris (N = 18) Nielsen (N = 21) Final GFR Rate of Decline [Trial End (1–6 years)] 136 154 Bakris GL & Weir M Arch Intern Med. 2000:160:685-693 Effect Of Early And Late Changes In GFR When Blood Pressure Is Controlled with an ACE Inhibitor ©2006. American College of Physicians. All Rights Reserved.

Most Likely Etiologies for Increasing Serum Creatinine

Volume Depletion

Heart Failure

Bilateral Renal Artery Stenosis

Tarif N and Bakris GL. IN: Johnson R and Freehally J (eds.) Principles of Nephrology Mosby & Co. London, 2000 pp. 40.1-12, Ashgar A & Bakris, G Primer in Kidney Disease , 2005 ©2006. American College of Physicians. All Rights Reserved.

General Concept

A rise in serum creatinine of up to 30% of baseline ( given baseline up to 3 mg/dl) that remains stable in the absence of hyperkalemia ([K+] > 6) correlates with slower renal disease progression.

Intensive Multiple Risk Factor Management Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%). * Death from CV causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease. † Behavior modification and pharmacologic therapy. Primary Composite End Point* (%) Months of Follow-up 60 40 20 12 24 36 48 60 72 84 96 Conventional Therapy Intensive Therapy † 20% Absolute Risk Reduction N=160; follow-up = 7.8 years Patients with Type 2 Diabetes and Microalbuminuria

Aggressive treatment of † :

Microalbuminuria with

ACEIs, ARBs, or combination

Hypertension

Hyperglycemia

Dyslipidemia

Secondary prevention of CVD

Percentage of Adults with Diabetes Who Achieved Recommended Goals of Cardiovascular Risk Factors in NHANES Saydah S et.al JAMA 2004;291:335 % ©2006. American College of Physicians. All Rights Reserved.

( if systolic BP > 20 mmHg above goal ) START with ACEI or ARB/thiazide diuretic*) If BP Still Not at Goal (130/80 mm Hg) If BP Still Not at Goal (130/80 mm Hg) or If used CCB, Add Other Subgroup of CCB (ie, amlodipine-like agent if verapamil or diltiazem already being used and the converse) OR if  blocker used add CCB Add Vasodilator (hydralazine, minoxidil) OR Refer to a Clinical Hypertension Specialist If BP Still Not at Goal (130/80 mm Hg) Add Long Acting Thiazide Diuretic* If Blood Pressure >130/80 mm Hg in Diabetes or Chronic Kidney Disease with Any Level of Albuminuria Recheck within 2-3 weeks Recheck within 2-3 weeks Recheck within 4 weeks ( if systolic BP< 20 mmHg above goal ) Start ARB or ACE Inhibitor titrate upwards Add CCB or  blocker** (titrate dose upward) Ashgar and Bakris, Primer of Kidney Diseases, 2005 Consider low dose aldosterone antagonists# ©2006. American College of Physicians. All Rights Reserved.

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